MGPPI: multiscale graph neural networks for explainable protein–protein interaction prediction

Abstract

Protein-Protein Interactions (PPIs) involves in various biological processes, which are of significant importance in cancer diagnosis and drug development. Computational based PPI prediction methods are more preferred due to their low cost and high accuracy. However, existing protein structure based methods are insufficient in the extraction of protein structural information. Furthermore, most methods are less interpretable, which hinder their practical application in the biomedical field. In this paper, we propose MGPPI, which is a Multiscale graph convolutional neural network model for PPI prediction. By incorporating multiscale module into the Graph Neural Network (GNN) and constructing multi convolutional layers, MGPPI can effectively capture both local and global protein structure information. For model interpretability, we introduce a novel visual explanation method named Gradient Weighted interaction Activation Mapping (Grad-WAM), which can highlight key binding residue sites. We evaluate the performance of MGPPI by comparing with state-of-the-arts methods on various datasets. Results shows that MGPPI outperforms other methods significantly and exhibits strong generalization capabilities on the multi-species dataset. As a practical case study, we predicted the binding affinity between the spike (S) protein of SARS-COV-2 and the human ACE2 receptor protein, and successfully identified key binding sites with known binding functions. Key binding sites mutation in PPIs can affect cancer patient survival statues. Therefore, we further verified Grad-WAM highlighted residue sites in separating patients survival groups in several different cancer type datasets. According to our results, some of the highlighted residues can be used as biomarkers in predicting patients survival probability. All these results together demonstrate the high accuracy and practical application value of MGPPI. Our method not only addresses the limitations of existing approaches but also can assists researchers in identifying crucial drug targets and help guide personalized cancer treatment.